BackgroundEpidermal growth factor receptor EGFR mutations, including a known exon 19 deletion 19 del and exon 21 L858R point mutation L858R mutation, are strong predictors of the response to EGFR tyrosine kinase inhibitor EGFR-TKI treatment in lung adenocarcinoma. However, whether patients carrying EGFR 19 del and L858R mutations exhibit different responsiveness to EGFR-TKIs and what are the potential mechanism for this difference remain controversial. This study aimed to investigate the clinical outcomes of EGFR-TKI treatment in patients with EGFR 19 del and L858R mutations and explore the genetic heterogeneity of tumors with the two mutation subtypes.

MethodsOf 1127 patients with advanced lung adenocarcinoma harboring EGFR 19 del or L858R mutations, 532 received EGFR-TKI treatment and were included in this study. EGFR 19 del and L858R mutations were detected by using denaturing high-performance liquid chromatography DHPLC. T790M mutation, which is a common resistant mutation on exon 20 of EGFR, was detected by amplification refractory mutation system ARMS. Next-generation sequencing NGS was used to explore the genetic heterogeneity of tumors with EGFR 19 del and L858R mutations.

ResultsOf the 532 patients, 319 60.0% had EGFR 19 del, and 213 40.0% had L858R mutations. The patients with EGFR 19 del presented a significantly higher overall response rate ORR for EGFR-TKI treatment 55.2% vs. 43.7%, P = 0.017 and had a longer progression-free survival PFS after first-line EGFR-TKI treatment 14.4 vs. 11.4 months, P = 0.034 compared with those with L858R mutations. However, no statistically significant difference in overall survival OS was observed between the two groups of patients. T790M mutation status was analyzed in 88 patients before EGFR-TKI treatment and 134 after EGFR-TKI treatment, and there was no significant difference in the co-existence of T790M mutation with EGFR 19 del and L858R mutations before EGFR-TKI treatment 5.6% vs. 8.8%, P = 0.554 or after treatment 24.4% vs. 35.4%, P = 0.176. In addition, 24 patients with EGFR 19 del and 19 with L858R mutations were analyzed by NGS, and no significant difference in the presence of multiple somatic mutations was observed between the two genotypes.

ConclusionsPatients with EGFR 19 del exhibit longer PFS and higher ORR compared with those with L858R mutations. Whether the heterogeneity of tumors with EGFR 19 del and L858R mutations contribute to a therapeutic response difference needs further investigation.